VTE ACHIEVEMENTS AND CHALLENGES: 2012 AND BEYOND Samuel Z. Goldhaber, MD Director, VTE Research Group Cardiovascular Division Brigham and Women s

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1 VTE ACHIEVEMENTS AND CHALLENGES: 2012 AND BEYOND Samuel Z. Goldhaber, MD Director, VTE Research Group Cardiovascular Division Brigham and Women s Hospital Professor of Medicine Harvard Medical School October 19, 2012

2 DISCLOSURES Research Support: Eisai; Daiichi; EKOS; Johnson & Johnson, Sanofi-Aventis Consultant: Baxter; Boehringer-Ingelheim; BMS; Daiichi; Eisai; Merck; Pfizer; Portola; Sanofi-Aventis

3 VTE ACHIEVEMENTS 1. Understanding common risk factors and pathophysiology of VTE and atherothrombosis 2. Appreciating that inflammation begets thrombosis, including VTE 3. Recognizing aspirin s role in preventing recurrent VTE 4. Realizing that oral monotherapy with rivaroxaban might revolutionize Rx

4 VTE is best considered as a pan-cardiovascular syndrome that includes: coronary artery disease, peripheral artery disease, and cerebrovascular disease.

5 CARDIOVASCULAR RISK FACTORS AND VTE (N=63,552 meta-analysis) RF RR Obesity 2.3 Hypertension 1.5 Diabetes 1.4 Cigarettes 1.2 High Cholesterol 1.2 (Ageno W. Circulation 2008; 117: )

6 (Piazza, Goldhaber. Circulation 2010;121: 2146) COMMON PATHOPHYSIOLOGY: VTE AND ATHEROSCLEROSIS

7 INFLAMMATORY TRIGGERS FOR VTE HOSPITALIZATION: A Case-Crossover Study 399 cases; database of 16,781 Risk Factor Risk vs. Control Infection 2.90 Transfusion Erythropoiesisstimulating Rx (Rogers MAM. Circulation 2012; 125: )

8 INFLAMMATION, INFECTION, VTE Inflammation stuns the endothelium of the vein and activates the vein wall. The vein is far more than a tube that transports blood to the lungs. The vein is a complex organ which can release agonists that trigger coagulation. (Tichelaar YIGV. Thromb Haemost 2012; 107: )

9 Veins: complex, highly regulated

10 Venous Endothelium- scanning electron micrograph Plt Denuded

11 Venous Endothelium- transmission electron micrograph EC BM SMC Adv

12 INFLAMMATION AND THROMBOSIS Inflammation, platelet hyperactivity, hypercoagulability, and endothelial dysfunction contribute to venous thrombosis. Thrombin is an inflammatory agonist. The platelet is a cluster bomb for preformed inflammatory markers.

13 Inflammation and Thrombosis Thrombin Resting Endothelial Cell Activated Endothelial Cell Reactive Oxygen Species Resting Smooth Muscle Cell Resting Platelet Aspirin xxxx xxxx Activated Degranulating Platelet Activated Macrophage Tissue Factor Procoagulant Pro-inflammatory Cytokines Proliferating Modulated Smooth Muscle Cell Pro-inflammatory Mediators (e.g., CD40L, RANTES, IL-6) Lipid mediators Of inflammation Croce K, Libby P. Intertwining of thrombosis and inflammation in atherosclerosis. Curr Opin Hematol. 2007;14:55-61

14 Inflammation Thrombosis Inflammation & Thrombosis: The clot thickens Libby & Simon Circulation 2001

15 ASA and Prevention of VTE Venous thrombi: fibrin, platelets, red cells, leukocytes. Environment: stasis, low oxygen tension, oxidative stress, proinflammatory gene up-regulation, impaired endothelial-cell regulatory capacity. Platelets: release polyphosphates, microparticles, proinflammatory mediators, and interact with neutrophils to generate DNA histone granule complexes. (Becker RC. NEJM 2012; 366: 2028)

16 ASPIRIN STUDY HYPOTHESIS After 6-12 months of anticoagulation for idiopathic, unprovoked PE or DVT, can baby aspirin 100 mg daily subsequently prevent recurrent VTE compared with placebo?

17 (Becattini C et al. NEJM 2012; 366: ) RISK OF RECURRENT VTE: ASPIRIN (N=205) VS. PLACEBO (N=197) Placebo: 43/197=11.2%/yr; Aspirin: 28/205=6.6%/yr

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20 STUDY CONCLUSIONS About 20% of patients with venous thrombosis or embolism but no defined risk factors have a recurrence within the first 2 years after stopping anticoagulation therapy. These authors report that 100 mg of aspirin a day nearly halved the risk of recurrence, with no increase in bleeding.

21 Antidote Yes No WARFARIN VS. NEW AGENTS Features Warfarin New Agents Onset Slow Rapid Dosing Variable Fixed Food effect Yes No Drug interactions Many Few INR Monitoring Yes No Half-life Long Short

22 SITES OF ACTION Steps in Coagulation Coagulation Pathway Drugs Initiation TF/VIIa X IX Propagation Fibrin formation IXa VIIIa Va Xa II IIa Rivaroxaban Apixaban Edoxaban Betrixaban Dabigatran Fibrinogen Fibrin (Hankey GJ and Eikelboom JW. Circulation 2011;123: )

23 EINSTEIN DVT/PE PROGRAM EINSTEIN-DVT (Confirmed DVT without PE) Rivaroxaban 15 mg BID for 3 weeks; then 20 mg once daily R EINSTEIN-PE (Confirmed PE without DVT) Enoxaparin BID > 5 Days + VKA to target INR = 2.5 (range 2-3) Primary Outcome: Symptomatic recurrent VTE

24 Event Rate Dec d 32%; P=0.08 (EINSTEIN-DVT. NEJM 2010; 363: 2499) (N=2,449) Immediate initiation with rivaroxaban; No parenteral anticoagulant given. Event Rate Dec d 82% EINSTEIN Extension Study clinical equipoise ; 1 of 4: provoked DVT. (N=1,196)

25 EINSTEIN- PE Symptomatic Recurrent VTE (Efficacy) (N=4,832) Clinically Significant Bleeding Major (P=0.003) Bleeding (P=0.003) [The EINSTEIN PE Investigators. N Engl J Med 2012; 366: ]

26 CHEST ACCP GUIDELINES 2012: DVT/PE (9 TH EDITION) For acute DVT or PE, we recommend initial parenteral anticoagulation (Grade 1B) or anticoagulation with rivaroxaban.

27 VTE CHALLENGES 1. Is catheter-based Rx warranted to prevent PTS after iliofemoral DVT? 2. What is the optimal duration of anticoagulation? 3. Should we revise and liberalize indications for IVC filters? 4. Which Medical Service patients should be discharged home on extended duration VTE prophylaxis?

28 POST THROMBOTIC SYNDROME Venous ectasia Hyperpigmentation Venous ulcer Edema Skin induration Venous ectasia

29 PTS RATES: DVT treated with AC + compression Author/Yr N Journal 2-yr PTS Prandoni Ann Intern Med 23% Brandjes Lancet 23% Prandoni Ann Intern Med 25% Partsch Int Angiol 46% Van Dongen J Thromb Haemost 30%

30 THE OPEN VEIN HYPOTHESIS Does immediate clot removal speed relief of initial DVT symptoms, save the venous valves, and prevent PTS?

31 MECHANISM OF PTS PREVENTION? Does the initial clot burden and/or post- PCDT residual clot burden predict the long-term risk of PTS? Does PCDT reduce valve injury? ATTRACT will assess pre- and post-pcdt clot burden and late valvular reflux.

32 Publication (Lancet 2012: 379: 31-38)

33 Primary outcomes Additional CDT (n=90) Standard (n=99) p- value* n % (95% CI) n % (95% CI) 24 months Post-thrombotic syndrome ( ) ( ) Absolute Risk Reduction = 14.5% Number Needed to Treat = 7 (Lancet 2012: 379: 31-38) *Unadjusted Chi-square test Results

34 Results Baseline 2 weeks Safety 20 bleeding complications related to CDT 5 clinically relevant 3 major Compartment syndrome of the calf surgery Abdominal wall haematoma blood transfusion Inguinal puncture site haematoma CDT stopped No deaths, pulmonary embolisms, cerebral haemorrhages or other complications with a permanently impaired outcome No bleeding complications in control patients

35 ATTRACT TRIAL (N=692): (ILIO)FEMORAL DVT STUDY ENROLLMENT PRE-RANDOMIZATION PROCEDURES RANDOMIZATION (1:1 Ratio) CONTROL ARM PCDT ARM LONG-TERM TREATMENT FOLLOW-UP

36 (Prandoni. High VTE Recurrence Rate Haematologica 2007; 92: ) (N=1,626 DVT patients)

37 RISKS FOR RECURRENCE Unprovoked e.g., long-haul travel Strong FH; PMH of VTE Lupus anticoagulant, protein C or S deficiency (Eur Heart J 2008; 29: 2276) Cancer Male (McRae S. Lancet 2006; 368: 371) Presentation with PE Symptoms (Eichinger. Arch Intern Med 2004;164: 92)

38 DOES HYPERCOAGULABILITY PREDICT RECURRENT VTE? Probably: lupus anticoagulant, protein C or S deficiency No Evidence: heterozygous Leiden or prothrombin gene mutation (European Heart Journal 2008; 29: )

39 OPTIMAL DURATION STRATEGY Acute PE or DVT Provoked Gray Zone Unprovoked 3-6 Months Rx Individualize Rx Consider Lifelong Rx Consider past/family VTE history, gender, recanalization of leg veins on U/S, hypercoagulability, patient preference (Goldhaber, Piazza. Circ 2011; 123: )

40 CHEST ACCP GUIDELINES 2012: DURATION OF RX If provoked by surgery or a nonsurgical transient risk factor, anticoagulation for 3 months (Grade 1B). If unprovoked with low to moderate bleeding risk, we suggest extended anticoagulant therapy rather than 3 months (Grade 2B).

41 CANCER/ RECURRENT VTE Probability of Recurrent VTE, % Lee et al. NEJM 2003; 349: Recurrent VTE Risk reduction = 52% p-value = WARFARIN DALTEPARIN Days Post Randomization

42 CHEST ACCP GUIDELINES 2012: DVT AND CANCER We recommend extended anticoagulant therapy rather than 3 months of therapy (Grade 1B). We suggest LMWH over VKA therapy (Grade 2B).

43 BARD RECOVERY INFERIOR VENA CAVAL FILTER

44 INCREASING USE OF VC FILTERS N=293,000 N=364,000 N=163,000 (Stein PD. Am J Med 2011; 124: )

45 IVC FILTERS AND IN-HOSPITAL MORTALITY (Stein PD. Am J Med 2012; 125: )

46 IVC FILTERS FOR PE: AHA PE Guidelines 2011 Contraindications to anticoagulation Recurrent PE despite adequate anticoagulation Very poor cardiopulmonary reserve, including those with massive PE (Circulation 2011; 123: )

47 EXTENDED VTE PROPHYLAXIS IN MEDICAL PATIENTS Study EXCLAIM (n = 5,963) MAGELLAN (n = 8,101) ADOPT (n = 6,528) Study conclusion VTE Major bleeding VTE Major bleeding VTE Major bleeding Net clinical benefit No No No Ann Intern Med 2010; 153: 8-18 ACC 2011 N Engl J Med 2011; 365:

48 TAKE HOME MESSAGES 1. VTE and atherothrombosis have common RFs and pathophysiology. 2. Inflammation promotes venous as well as arterial thrombosis. 3. Aspirin reduces recurrent VTE, though not as much as anticoagulation. 4. Rivaroxaban as oral monotherapy will revolutionize VTE management.

49 TAKE HOME MESSAGES 5. Pharmacomechanical catheter-based therapy may reduce or prevent PTS. 6. The optimal duration of anticoagulation after VTE remains uncertain. 7. IVC filter insertion is rapidly increasing, and observational data appear to support this practice among unstable patients. 8. We have not yet found the sweet spot for VTE prophylaxis of high risk Medical Patients after hospital discharge.

50 VENOUS THROMBOEMBOLISM ACHIEVEMENTS AND CHALLENGES: 2012 AND BEYOND Samuel Z. Goldhaber, MD Achievement #1: Understanding common risk factors and pathophysiology of venous thromboembolism (VTE) and atherothrombosis. VTE is best considered as a pan-cardiovascular syndrome that includes coronary artery disease, peripheral artery disease, and cerebrovascular disease. The risk factors for VTE are similar to classic cardiovascular risk factors and include obesity, hypertension, diabetes, cigarette smoking, and high cholesterol. The pathophysiology is also similar for both VTE and atherothrombosis: inflammation, hypercoagulability, and endothelial injury. VTE. Achievement #2: Appreciating that inflammation begets thrombosis, including Infection, blood transfusion, and administration of erythropoiesis-stimulating agents are associated with inflammation, which stuns the endothelium of the vein and activates the vein wall. The vein is a complex organ which can release agonists that trigger coagulation. Thrombin is an inflammatory agonist. The platelet is a cluster bomb filled with preformed inflammatory markers. Venous thrombi contain fibrin, red cells, leukocytes, and platelets. The venous thrombus resides in an environment of stasis, low oxygen tension, oxidative stress, proinflammatory gene up-regulation, and impaired endothelial-cell regulatory capacity. Platelets can release polyphosphates, microparticles, and proinflammatory mediators. They can interact with neutrophils to generate DNA-histone-granule complexes. Achievement #3: Recognizing aspirin s role in preventing recurrent VTE. In a randomized controlled trial of about 400 patients who had suffered idiopathic VTE and had received 6-12 months of standard anticoagulation, subjects were randomized to extended treatment with aspirin 100 mg daily versus placebo. Approximately 20% in the placebo group suffered a recurrent VTE within the ensuing 2 years. However, aspirin 100 mg daily halved the risk of recurrence, with no increase in bleeding. Achievement #4: Realizing that oral monotherapy with rivaroxaban might revolutionize the therapy of acute DVT and PE.

51 In 4,832 acute PE patients, treatment was randomized to rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily versus standard therapy with enoxaparin as a bridge to warfarin. Rivaroxaban was noninferior to standard therapy for preventing symptomatic recurrent VTE. However, rivaroxaban halved the rate of major bleeding compared with standard therapy. 4 Challenges: 1) Will pharmacomechanical catheter-based therapy (a combination of physical clot disruption plus low-dose thrombolytic therapy) of large femoral or iliofemoral DVT reduce the severity or prevent post-thrombotic syndrome of the legs? 2) What is the optimal duration of anticoagulation after VTE? 3) Should we liberalize criteria for IVC filter insertion, especially because observational databases suggest a mortality reduction among PE patients who receive thrombolytic therapy and among patients who are unstable? 4) Which high risk for VTE Medical Service patients should be discharged home on extended duration VTE prophylaxis, where the risk of thrombosis outweighs the risk of bleeding? 1-16 REFERENCES 1. Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363: Becattini C, Agnelli G, Schenone A, et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med 2012;366: Becker RC. Aspirin and the prevention of venous thromboembolism. N Engl J Med 2012;366: Buller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366: Enden T, Haig Y, Klow NE, et al. Long-term outcome after additional catheterdirected thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial. Lancet 2012;379: Goldhaber SZ, Piazza G. Optimal duration of anticoagulation after venous thromboembolism. Circulation 2011;123:664-7.

52 7. Goldhaber SZ, Leizorovicz A, Kakkar AK, et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med 2011;365: Hankey GJ, Eikelboom JW. Dabigatran etexilate: a new oral thrombin inhibitor. Circulation 2011;123: Hull RD, Schellong SM, Tapson VF, et al. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med 2010;153: Jaff MR, McMurtry MS, Archer SL, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011;123: Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e419S- 94S. 12. Piazza G, Goldhaber SZ. Venous thromboembolism and atherothrombosis: an integrated approach. Circulation 2010;121: Rogers MA, Levine DA, Blumberg N, et al. Triggers of hospitalization for venous thromboembolism. Circulation 2012;125: Stein PD, Matta F, Hull RD. Increasing use of vena cava filters for prevention of pulmonary embolism. Am J Med 2011;124: Stein PD, Matta F, Keyes DC, et al. Impact of vena cava filters on in-hospital case fatality rate from pulmonary embolism. Am J Med 2012;125: Tichelaar YI, Kluin-Nelemans HJ, Meijer K. Infections and inflammatory diseases as risk factors for venous thrombosis. A systematic review. Thromb Haemost 2012;107: